Targeting the PHF8/YY1 axis suppresses cancer cell growth through modulation of ROS

High levels of mitochondrial reactive oxygen species (mROS) are linked to cancer development, which is tightly controlled by the electron transport chain (ETC). However, the epigenetic mechanisms governing ETC gene transcription to drive mROS production and cancer cell growth remain to be fully char...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2024-01, Vol.121 (2), p.e2219352120-e2219352120
Main Authors: Wu, Xiao-Nan, Li, Jia-Yuan, He, Qi, Li, Bo-Qun, He, Yao-Hui, Pan, Xu, Wang, Ming-Yue, Sang, Rui, Ding, Jian-Cheng, Gao, Xiang, Wu, Zhen, Liu, Wen
Format: Article
Language:English
Subjects:
Ablation
Cell growth
Cell Transformation, Neoplastic
Colon
Colon cancer
DNA methylation
Electron transport
Electron transport chain
Epigenetics
Gene expression
Gene regulation
Histone Demethylases - metabolism
Histones
Histones - metabolism
Humans
Lung cancer
Lung Neoplasms - genetics
Nuclear safety
Reactive oxygen species
Reactive Oxygen Species - metabolism
Transcription Factors - metabolism
Xenotransplantation
YY1 protein
YY1 Transcription Factor - genetics
YY1 Transcription Factor - metabolism
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Summary:High levels of mitochondrial reactive oxygen species (mROS) are linked to cancer development, which is tightly controlled by the electron transport chain (ETC). However, the epigenetic mechanisms governing ETC gene transcription to drive mROS production and cancer cell growth remain to be fully characterized. Here, we report that protein demethylase PHF8 is overexpressed in many types of cancers, including colon and lung cancer, and is negatively correlated with ETC gene expression. While it is well known to demethylate histones to activate transcription, PHF8 demethylates transcription factor YY1, functioning as a co-repressor for a large set of nuclear-coded ETC genes to drive mROS production and cancer development. In addition to genetically ablating PHF8, pharmacologically targeting PHF8 with a specific chemical inhibitor, iPHF8, is potent in regulating YY1 methylation, ETC gene transcription, mROS production, and cell growth in colon and lung cancer cells. iPHF8 exhibits potency and safety in suppressing tumor growth in cell-line- and patient-derived xenografts in vivo. Our data uncover a key epigenetic mechanism underlying ETC gene transcriptional regulation, demonstrating that targeting the PHF8/YY1 axis has great potential to treat cancers.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2219352120